Levothyroxine sodium is relatively stable in pure form, but pharmaceutical preparations containing levothyroxine hormone exhibit a relatively short shelf life, even when in solid unit dose form, and most particularly under conditions of high humidity and temperature.
U.S. Pat. No. 5,225,204 is directed to improving the stability of levothyroxine sodium. The patent claims stability is achieved in several embodiments. The first embodiment relates to mixing a commercial grade of levothyroxine sodium with polyvinyl pyrrolidone (PVP), at least partially dissolving the resulting mixture in a polar organic solvent, and adding a cellulose carrier compound. The solvent is removed by drying, to produce a resulting fine powder said to be a stable complex of levothyroxine sodium and polyvinyl pyrrolidone disbursed on the surface of the cellulose carrier component.
In a second embodiment of the '204 patent, the PVP is replaced by a Poloxamer.
In a third embodiment of the '204 patent, the levothyroxine sodium is at least partially dissolved in a polar organic solvent in the absence of PVP and Poloxamer, and the cellulose carrier is added, after which the solvent is removed to leave the levothyroxine sodium adsorbed on the cellulose carrier.
A fourth embodiment of the '204 patent describes that stabilized levothyroxine sodium may be prepared in a dry state by mixing levothyroxine sodium with a cellulose complexing agent and subsequently combining this mixture with a cellulose carrier. Specifically, it is described in the '204 patent that levothyroxine sodium can also be effected by initially mixing it with a cellulose tableting agent using the geometric dilution technique and the same, or a second, cellulose tableting agent, such as microcrystalline cellulose, is added to the dry mixture. The tableting agent is described as a carrier or adsorbing agent. Other tableting aids such as hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose and hydroxypropylmethyl cellulose. These polymer cellulose compounds are known to be insoluble or partially soluble
U.S. Pat. No. 5,225,204 indicates that most of the commonly used excipients may be mixed with the stabilized levothyroxine sodium, but certain carbohydrate excipients which are known as degrading agents of levothyroxine sodium should be avoided. These excipients include dextrose, starch, sugar and lactose.
Although U.S. Pat. No. 5,225,204 claims that the resulting pharmaceutical compositions are stable compositions, no stability data was presented. Examples 1 and 2 of the U.S. Pat. No. 5,225,204 were repeated (in repeating example 1 of U.S. Pat. No. 5,225,204, K-30 Plasdone was used instead of C-15 Plasdone, as C-15 Plasdone was not available. This difference is believed trivial, since the differences between the two products is only a molecular weight difference), and the resulting preparations were subjected to stability tests at ambient room temperature (ART) and at 30.degree. C. and 40.degree. C. with no humidity control. The resulting stability data are set forth below.
______________________________________ EXAMPLE 1 OF U.S. PAT. NO. 5,225,204 Condition Interval % Actual (S.D.) ______________________________________ Initial Initial 100.0 ART 1 month 92.3 .+-. (6.1) ART 2 months 88.1 .+-. (2.7) ART 3 months 87.2 .+-. (11.9) 30.degree. C. 1 month 86.1 .+-. (5.1) 30.degree. C. 2 months 95.3 .+-. (3.9) 30.degree. C. 3 months 87.8 .+-. (5.6) 40.degree. C. 1 month 95.0 .+-. (1.8) 40.degree. C. 2 months 94.7 .+-. (5.7) 40.degree. C. 3 months 91.9 .+-. (4.2) ______________________________________
______________________________________ EXAMPLE 2 OF U.S. PAT. NO. 5,225,204 Condition Interval % Actual (S.D.) ______________________________________ Initial Initial 97.0 .+-. (0.4) ART 1 month 89.7 .+-. (2.3) ART 2 months 68.3 .+-. (1.9) ART 3 months 61.4 .+-. (1.9) 30.degree. C. 1 month 88.3 .+-. (1.6) 30.degree. C. 2 months 71.3 .+-. (1.3) 30.degree. C. 3 months 64.2 .+-. (0.1) 40.degree. C. 1 month 89.5 .+-. (0.6) 40.degree. C. 2 months 64.1 .+-. (0.1) 40.degree. C. 3 months 62.5 .+-. (1.2) ______________________________________
Example 1 of U.S. Pat. No. 5,225,204 involved the use of PVP. A non-uniform granulation was obtained, which was difficult to convert into solid dosage form. Unknown peaks were visible in the stability samples, and the peaks are speculated to be due to an adduct formed in solution between levothyroxine sodium and PVP.
Example 2 of U.S. Pat. No. 5,225,204 was prepared using dry mixing of levothyroxine sodium with hydroxypropyl cellulose, with subsequent combination of this mixture with a microcrystalline cellulose carrier. The stability test results are substantially worse than commercial products which were commercially available at the time the application which matured into U.S. Pat. No.5,225,204 was filed.